JPH01250372A - Cyclic anti-inflammatory derivative of di-tert-bytylphenol compound - Google Patents

Abstract

The present invention involves compounds having the structure: <CHEM> (a) -A- is selected from the group consisting of -CH2-, - @@-, and -@-; (b) -Y is selected from certain low molecular weight alkyl chains which terminate in specific unsaturated functional groups: -C IDENTICAL CH, - @=CH2, -@=C=CH2 and aldehydes in the form of their acetals; pharmaceutical compositions comprising such compounds; and methods for treating inflammation by administering such compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION BACKGROUND OF THE INVENTION The present invention relates to novel specifically substituted derivatives of di-tert-butylphenol compounds that are effective as anti-inflammatory, analgesic and/or antipyretic agents. Furthermore, the present invention relates to pharmaceutical compositions useful for treating diseases involving inflammation, pain and/or fever. Finally, the invention relates to a method for treating diseases characterized by inflammation.

Research into new non-steroidal anti-inflammatory ("N5AI") agents over the past 10-20 years has involved testing thousands of compounds for efficacy as anti-inflammatory agents by various researchers and companies.

Research has raised a number of questions, but has provided few answers as to how and why some compounds are effective and others are not, particularly with respect to substituted di-tert-butylphenol compounds. This study, and its results and issues, will be discussed with K.
F. Swingle et al.
Anti-inflammatory and anti-rheumatic agents (Anti-!nl'la+
g+gatory and Anti-rheu+ga
ticDrugs), Volume ■ [K. D. Ra1nsf'ord, ed.
CRC Press, Inc.;
1985], Chapter 4, pp. 105-126.
Anti-inflammatory activity of antioxidants” (“Antl-1nfl
amsatory Actlty of Antl
-oxtdants”), the disclosure of which is incorporated herein by reference.

Despite significant efforts to date to identify N5AI agents, no new compounds and compositions have been identified that are effective in treating inflammation and inflammatory diseases such as rheumatoid arthritis and osteoarthritis. The need to do so continues. It is therefore an object of the present invention to provide compounds that are effective anti-inflammatory agents and pharmaceutical compositions containing these compounds. Another object of the invention is to provide a method for treating diseases characterized by inflammation.

Another object of the invention is to provide one or more of the following uses: anti-inflammatory agents, analgesics, antipyretics, anti-arthritic agents, bone repair agents.
d1f)'1ng agent), an immunomodulator, an antilipemic agent, an absorption inhibitor, or a drug for combating ischemic cell damage, and pharmaceutical compositions containing these compounds. .

Yet another object of the invention is to provide compounds and compositions containing these compounds that have high potency, low toxicity (e.g. low gastrointestinal irritation), back-action time and/or good therapeutic index. It is.

These and other purposes will become apparent from the detailed description below.

SUMMARY OF THE INVENTION The present invention provides an anti-inflammatory agent, an analgesic agent,
Specific substituted cyclic derivatives of 2,6-tert-butylphenol compounds that are effective as antipyretics, antioxidants, antiarthritic agents, immunomodulators, antilipemic agents, antiresorptive agents or agents against ischemic cell damage. Regarding. These phenyl compounds are substituted at the 4-position by a low molecular weight alkyl chain terminating with a specific unsaturated functional group. These unsaturated functional groups are -C-CH, -C-CH2, -C-C-CH2 and aldehydes in acetal form.

The invention further relates to pharmaceutical compositions. These compositions are
Contains a compound of the invention and a pharmaceutically acceptable carrier.

Finally, the invention also relates to a method for the treatment of diseases characterized by inflammation, such as rheumatoid arthritis and osteoarthritis, in humans or lower animals. Such methods are characterized by administering a safe and effective amount of a compound or composition of the invention to a human or lower animal in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION Anti-inflammatory agents Compounds useful in the present invention include 2,
A specific substituted cyclic derivative of the 6-tert-butylphenol compound.

selected from. -C-CH and acetal terminal functional groups are preferred.

Specifically, the compounds of the present invention have the following structure: In this structure, -A- is -CH2-1, -A- is CH
2 or -〇-, and the most preferred -A- is -CH2-
It is.

-Y is a terminal unsaturated group selected from the group consisting of: 1) (CR12), C-C-H (n is 1 to about 6
(m is an integer of 1 to about 5, and m + n is an integer of 1 to about 5); (n is O or 1, and m is an integer of 1 to about 5); 5)-(CR) CR3-CH2 (n is an integer from about 2 to about 6); (n is an integer from O to about 5); (m is an integer from 1 to about 3); (n is an integer from 0 to about 3); 9) -(CR2). -CR-C-CH2 (n is 0 to about 6
(m+n is an integer of 0 to about 5; preferably m-0 or 2); (n is an integer of 0 to about 3); 12) -(CR2), -CH( ZR) 2 (n is 1
and (n is an integer from 1 to about 5, m is an integer from 0 to about 4, and m+n is an integer from about 1 to about 5; m-0 or 2 is preferred); In these substituted -Y groups, each -R1 is -CO
R3, -C(0)NR32, selected from the group consisting of straight chain or branched saturated alkyl groups having 1 to about 3 carbon atoms and straight chain or branched unsaturated alkyl groups having 1 to about 3 carbon atoms Alternatively, two -R1's on the same carbon atom are -0 or -CR32. Preferably -
R1 is -H, -OH, methyl or ethyl, or two -R1 on the same carbon atom are 10 or -CH2
and more preferably about 2 or less -R groups are other than -H. Most preferably all -R1 groups are -H.

Each -R is independently NR1-〇R3, NR3 2, -NR", -N (R) C(0) R3, -0CR3, -Co
R, -C(0) NR carbon atom 12
selected from the group consisting of straight chain or branched saturated alkyl groups having from 2 to about 3 carbon atoms and straight chain or branched unsaturated alkyl groups having from 1 to about 2 carbon atoms; -R2 is 10 or -CR32. Preferably, -R2 is -H, -OH
, methyl or ethyl, or two -R2 on the same carbon atom are 10 or -CH2, more preferably up to about two -R groups are other than -H. all NRs
Most preferably, the two groups are -H.

Each -R3 is independently selected from the group consisting of -H, methyl and ethyl. Preferred -R3 is -H.

Each -R is independently selected from the group consisting of -CH3 and -CH2CH3, or -R and both -R4 together are selected from -(CH)- and -(CH2)3-. are bonded to form a cyclic acetal that serves as a single group. Both -R groups are methyl or both NR4
Preferably, the groups taken together are -CH2CH2-. Most preferably both NR4 groups are methyl.

Each -Z- is independently selected from the group consisting of 10-1-S-1-NH- and -NR4-. −Z− is −〇−
or -8-, and most preferably both -Z- groups are the same atom selected from 10- or -S-.

Particularly preferred acetal groups (i.e. -CH(ZR)2M) are CH(OMe)2,
It is. The most preferred specific acetal is preferred -Y
The group is a group having a terminal -CCH or acetal functionality: 1)-(CR2)nC-CH (where n is an integer from 1 to about 6; n is an integer from about 5) (n is an integer from 0 to about 3); (n is 0 or 1); 5) -(CR) -CH(ZR) 2 (nn is an integer from 1 to about 6); ( (n is an integer from 1 to about 5); (n is an integer from 1 to about 3);

The most preferred -Y groups are: (n is an integer from 0 to about 3); (n is an integer from 1 to about 5); and especially 10 is an integer from about 5 to (more preferably an integer from 1 to about 4, most preferably 10-3).

Compounds of the invention include their pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to compounds in toxicologically acceptable salt form that have the same general pharmacological properties as the proton form from which they are derived. Pharmaceutically acceptable salts include alkali metals (e.g. sodium and potassium), alkaline earth metals (e.g. calcium and magnesium), non-toxic heavy metals (e.g. stannous and indium), ammonium and low molecular weight salts. There are substituted ammonium (mono, di and trimethyl or ethyl ammonium) salts. Sodium, potassium and ammonium salts are preferred.

The compounds of the invention may be used as one or more of the following: anti-inflammatory agents, analgesics, antipyretics, anti-arthritic agents, anti-resorptive agents, immunomodulators, antilipemic agents, anti-aging agents or for ischemic cell damage. has utility as a drug against one or more of the following diseases or conditions: rheumatoid arthritis, osteoarthritis, bone loss disease, periodontal disease, gingivitis, allergic rhinitis, asthma, Hay fever, shock lungs and pulmonary edema, bronchitis, emphysema, signs and symptoms associated with colds and influenza, Crohn's disease, inflammatory bowel disease, myocardial infarction (reperfusion)
ischemic disorder due to phlegmon reper [usion], post-ictal hematopoietic disorder to the brain, contact dermatitis, dry snoring, atopic dermatitis, urticaria rash, hives, allergic eczema,
allergic conjunctivitis, atherosclerosis, anaphylactic shock, cerebral stroke disorders, gout, organ transplant rejection, tissue damage and burns, CNS inflammatory reactions (i.e., multiple sclerosis symptoms), despondency, and hypercholesterolemia. It is also potentially useful for therapy.

Testing of these compounds in animals is performed using a variety of assays known to those skilled in the art to determine and evaluate pharmacological activity. For example, the anti-inflammatory activity of compounds can be conveniently demonstrated using assays designed to test the ability of these compounds to antagonize the local edema characteristic of inflammatory responses. Examples of such known test methods include the carrageenan rat edema test, the oxacillone-induced inflammation mouse ear test, and the arachidonic acid-induced inflammation mouse ear test. Antipyretic activity was tested using rat models known in the art, and analgesic activity was tested in models known in the art, such as the acetylcholine model in mice, the Randall Itto model in rats, and in mice or rats. Tested by hot-plate test. Another useful test method known in the art is the adjuvant arthritis test, which is a useful model for evaluating anti-inflammatory or anti-arthritic activity and anti-resorptive activity in non-acute chronic models.

These and other test methods suitable for pharmacological activity are described in U.S. Pat. No. 4,130,666 to Moore, issued December 19, 1978; U.S. Patent No. 4,440°784 issued on April 3; Japanese Patent Application No. 85154315 published on March 28, 1985 by Karami et al.; September 1982 by Yamanouchi Pharmaceutical Co., Ltd. European Patent Application No. 59,090, published on April 1; “Prostaglandin and leukotriene synthesis in arachidonic acid-inflamed mouse ears”, The Journal of Investigative Dermatology -(The Jour
nal of'InvestigativeDerm
84, pp. 253-256.

1985; U.S. Patent No. 4,431,656 issued February 14, 1984 to Karami et al.;
“Anti-inflammatory activity of antioxidants” by F. Swingle et al., Anti-inflammatory and Anti-Eumatic Agents, Vol.
Reinsford, ed., CRC Brace, 1985); Adam Kiwicz et al., Canadian Journal of Biochemistry and Biogeology, Vol. 33, p. 332, 1955 (Ada.
Canadian
Journal ofBIochea+fstry
and Physology, 33.332 (19
55)); Serui, British φ Medicinal Journal, Vol. 2, p. 1129, 1949 (S
elye, Br1tish Medlclnal J
2.1129 (1949); and Winter, Proceedings of Experimental Biology and Medicine No. 111.
Volume, page 554.

1962 (Wlnier, Proceeding
or Experimental BIology
and Medicine, 111.554 (19
82)), the disclosures in all such patents and articles are incorporated herein by reference.

The compounds of this invention are prepared from commercially available materials. Although the synthetic techniques disclosed for the compounds of the present invention and related compounds can be adapted by skilled chemists for the preparation of the present compounds, such synthetic techniques are described, for example, in U.S. Pat.
, No. 130,666 and No. 4,440,784, Japanese Patent Application No. 85154315, and Loumans (Lomans) filed on June 27, 1986.
co-pending U.S. Pat. No. 879.8 to MaLthevs and Miller
No. 63 Specification 1F (U.S. Pat. No. 4,708,966, issued November 24, 1987). and several other patent specifications and publications, all of which are incorporated herein by reference. Representative methods for synthesizing compounds of the invention are shown in the examples below.

Compounds of the invention typically comprise from about 0.1 to about 99.9%, preferably from about 20 to about 80%, by weight of the pharmaceutical compositions of the invention.
% by weight, most preferably from about 40 to about 80% by weight.

The compounds of the present invention are effective anti-inflammatory agents, as evidenced by the animal test results presented in the Examples below. Furthermore, some of the compounds of the present invention surprisingly exhibit anti-inflammatory activity at very low dosage levels. Surprisingly, some of the compounds of the present invention appear to have low toxicity, including very low gastrointestinal irritation, even when administered. In addition, some of the compounds of the present invention are expected to be long-acting, which is why the typical 4 index for most commercially available anti-inflammatory agents
Compared to dosing every ~6 hours, less frequent dosing is possible with the compounds of the invention.

Pharmaceutically Acceptable Carriers In addition to the anti-inflammatory agents described above, the pharmaceutical compositions of the present invention inherently contain a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler diluents or encapsulating substances suitable for administration to humans or lower animals. As used herein, the term "compatibility" means that each of the pharmaceutical compositions is such that, under normal conditions of use, there is no interaction that would substantially reduce the pharmaceutical efficacy of the pharmaceutical composition. This means that the ingredients can be mixed with the anti-inflammatory agent and with each other.The pharmaceutically acceptable carrier must be of sufficiently high purity and sufficient to be compatible for administration to the human or lower animal to be treated. Of course, it must also have low toxicity.

Some examples of substances that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; its derivatives such as; powdered tragacanth; malt; gelatin;
Talc: stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil;
Polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar; alginic acid; pyrodiene-free water; isotonic saline; phosphate buffers - and other non-toxic compatible materials used in pharmaceutical formulations. Wetting agents, lubricants such as sodium lauryl sulfate, coloring agents, flavoring agents, excipients, tablet forming agents,
Stabilizers, antioxidants and preservatives may also be present.

Other compatible excipients and active agents (e.g. other
5AI agent, analgesic, muscle relaxant) may be present in the pharmaceutically acceptable carrier for the composition of the present invention.

The choice of a pharmaceutically acceptable carrier to be used in conjunction with the anti-inflammatory agents of the present invention is fundamentally determined by the manner in which the compound is administered. When the compound is injected, a preferred pharmaceutically acceptable carrier is sterile physiological saline containing a hemocompatible suspending side, the pH of which is about 7.4: J! J is arranged. Pharmaceutically acceptable carriers suitable for topical application include carriers suitable for creams, gels, tapes, and the like.

The preferred mode of administration of the compounds of this invention is oral. Accordingly, preferred unit dosage forms are tablets, capsules, etc. containing a safe and effective amount of an anti-inflammatory compound of the invention, where the safe and effective amount preferably ranges from about 10 to about 3500 ag;
More preferably about 25 to about 1000+++ g, most preferably about 25 to about 600 mg. Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Their selection depends on secondary considerations such as taste, cost, and storage stability which are not important for the purposes of the present invention and can be easily carried out by one skilled in the art.

Pharmaceutically acceptable carriers used in combination with the anti-inflammatory agents of the present invention are used in concentrations sufficient to provide a practical size that meets the dosage relationship. Overall pharmaceutically acceptable carriers include:
Pharmaceutical compositions of the invention have a weight range of about 0.1 to about 99.9%, preferably about 20 to about 80%, most preferably about 20% by weight.
It accounts for ~60% by weight.

Method for treating diseases characterized by inflammation Another aspect of the present invention is a method for treating diseases characterized by inflammation. Such methods are characterized by administering a safe and effective amount of the anti-inflammatory agent to a human or lower animal in need of such treatment.

The preferred mode of administration is oral, except for other known modes of administration, such as transdermal, mucosal (e.g., transdermal, transrectal, etc.) and parenteral (e.g., subcutaneous, intramuscular, articular, intravenous, etc.) can be considered similarly. Also included are ocular administration and inhalation. In this way, the specific administration method is not particularly limited, and can be administered orally,
It can be administered transdermally, transmucosally, sublingually, nasally, intramuscularly, intravenously, intraperitoneally, subcutaneously, and locally.

As used herein, the term "disease characterized by inflammation" refers to arthritis (e.g., rheumatoid arthritis, osteoarthritis, dry nail joints, juvenile arthritis, Reichl's syndrome, infectious arthritis, ankylosing arthritis). Conditions known to be associated with inflammation, such as spondylitis, systemic lupus erythematosus, and gout) and whether or not they are associated with an identifiable disease refer to the presence of relevant inflammation. Furthermore, diseases characterized by inflammation include oral cavity (e.g., inflammation associated with gingivitis or periodontal disease);
c Inflammation of the gastrointestinal tract including, for example, inflammation associated with inflammatory bowel disease); inflammation associated with skin diseases (eg psoriasis); and inflammation associated with the respiratory airways (eg pneumonia).

As used herein, the phrase "safe and effective amount" is defined as an amount that is within the scope of sound medical judgment and is sufficiently large to significantly ameliorate the symptoms being treated but avoid serious side effects. It means an amount of a compound or composition that is sufficiently small (with a reasonable benefit/risk ratio) to be effective. The safe and effective amount of anti-inflammatory drugs depends on the specific symptoms to be treated, the age and physical condition of the patient to be treated, the severity of symptoms, the duration of treatment, the type of concomitant therapy, the specific anti-inflammatory drugs used, and the use of Variations will vary depending on the particular pharmaceutically acceptable carrier used and similar factors within the knowledge and judgment of the attending physician. However, a single dose ranges from about 10 to about 3500+ ng
, about 0.2 to about 70 mg/kg body weight. A preferred single dose is about 25 to about 600 mg, or about 0.5 to about 600 mg.
Approximately 12 ttrg/kg body weight. One dose is 1
It can be administered up to about 6 times a day.

The following examples further describe and illustrate preferred embodiments falling within the scope of the invention. The examples are presented for illustrative purposes only and should not be construed as limiting the invention, as numerous variations thereof are possible without departing from its spirit and scope. . All temperature readings are in °C.

Compounds of the invention can be prepared according to the routes illustrated and described above. The compound number below is
They correspond to the compounds numbered in the figure.

Example 1 Preparation of 2 o-(t-butyl)phenol (1) 47. 5g
(316 mmol), 1,1-dichloro-2,
Add 100 ml of 2-difluoroethylene solution.

The flask is tightly stoppered at 0° C. and the mixture is warmed to room temperature and stirred vigorously for 48 hours. The reaction mixture is poured into water and extracted with petroleum ether. The combined organic phases are washed with saturated NaCl and dried (MgSO4).

83 by concentration and short-path distillation
．． Obtain 4g (93%) of 2: bp95”/1to
rr; IR (film): 2970 (m), 1445
(m), 1310 (s), 1265 (s).

1235 (s), 1175 (s), 1165 (s)
, 835 (s) , 755 (s) cm-'
;”H-NMR (CDCl 3. TMS) δ: 1.4
0 (s, 9H), 5.95 (t.

J=7Hz, IH), 7.0-7.5 (m, 4H).

Preparation of 3 in 875 ml of tetrahydrofuran (THF) 82, 2
A solution of 2 of g (291 m+gol) was added to 2.74 M n-butyllithium (n-BuLi) at -78°C.
) 640 ml (1.75 mol), maintaining the temperature below -60°C. Heat the mixture at -78°C.
Stir for an hour, then warm up very slowly to room temperature and stir it overnight. The reaction solution was recooled to -78°C,
And methyl disulfide 41. 1 g (436I
Add Ilol). The solution was warmed to 25°C and stirred for 2 hours, then 0. Pour into IN HCI. The aqueous portion was extracted with ether and the combined organic phases were dissolved in saturated NaHC.
03 and saturated NaCl and then dried (MgSO4). GC analysis of the reaction mixture showed a very clean reaction, with almost no presence of compounds other than 3. Volatile solvents are distilled off in the hood, and the pot temperature reaches about 110°C.

GC analysis at this point shows an approximately 321 mixture of 3 and the corresponding thioester derived from hydration of the triple bond. Approximately 3:1 mixture of 3 and the corresponding thioester by Kugelrohr distillation (oven temperature -110-140 °C, 0,5 torr) 43,5
g (approximately 68%) = (spectrum of pure 3)
IR (NEET): 3480 (m).

2960 (m), 1430 (s), 1225-1,
1 (m), 745 (s) cm, H-NMR (CD
Cl2. TMS) δ: 1.45 (s.

9H), 2. 50 (s, 3H), 6.2
5 (s.

IH), 6.80 (m, IH), 7.
25 (m.

2H).

4 Production 3 (containing about 25% thioester) 43.5g (about 193
IImol) and methanol and 3NH2S04 each 60
Reflux the mixture with 0 ml overnight. The reaction solution is concentrated to approximately half its original volume by distillation of the volatiles, then cooled to 25°C and concentrated by water aspirator in a hood (this operation removes all volatile sulfur by-products). ). Pour the concentrated reaction solution into water and extract with ether. The combined organic phases are washed with saturated NaHCO3 and saturated NaCl and then dried (MgS
O4). The volatiles are removed under reduced pressure and the crude lactone is recrystallized from hexane to yield 23.2 g of pure 4. The mother liquor was subjected to flash chromatography (10% EtOAc/
Hexane) to obtain an additional 2.01 g of 4. Total yield of 4 is 25.2g (69%): mp 99.5
-100'; IR (CDC13): 2965 (
s), 1795 (vs), 1430 (s), 1085
(s).

-1,1 1070(s) Cm, H-NMR (CDCl
2. TMS) δ: 1.40 (s.

9H), 3.65 (s, 2H), 7.15 (m.

3H); 13C-NMR (CDCl2.TMS) δ:
29°50, 32.56, 34.19°122.15,
123.54, 123.90° 125.81, 134.
Production of 16,152.65°174.03°5 in 100ml of THF3. sow (20,0ff
isol) 4 and iodomethane 5.0ml (80I
Add potassium t-butoxide (1 mol) at 0°C to a solution of
Add 5 to 6 g (50+nol) of BuOK) little by little. The mixture was stirred at 0 °C for 30 min, then 2
Warm to 5°C and stir for an additional 2 hours. The reaction solution was reduced to 0. lN
Pour into HCl and extract the aqueous layer with ether. The combined organic phases are washed with saturated NaHCO3 and saturated NaCl and then dried (MgS04). The crude concentrated reaction mixture is recrystallized from hexane to yield 2.21 g of pure 5. The mother liquor was distilled in a Kugelrohr oven at a temperature of -16
0°C, 0.5 torr) and further obtain 5 of 1.19 f. The total yield of 5 is 3.40g (78%): mp8
4-85°; IR (CDC13): 2970
(s).

1795 (vs), 1430 (s), 1280-1
．． 1 (s), 1055 (s)am, H-N
MR (CDC131TMS) δ: 1.40 (s.

9H), 1.50 (s, 6H), 7.15 (m.

3H); 13C-NMR (CDCl2 TMS) δ: [
Off resonance multiplicity (off'-rcs
onance mulNplIcity) ) 25.
38 (q).

29.58 (Q), 34.21 (s).

42.09 (s), 120.32 (d).

124.14(d), 125.59(d).

134.13 (s, 2 carbons), 150.11 (s
), 180.82 (s).

Preparation of 6 Lithium aluminum hydride in 50 ml of ether 1,
A solution of 14 g (30.0 mmol) was prepared at 0°C for 5.45
g (25,0+mol) of 5.

The reaction mixture is warmed to 25°C and stirred for 1 hour.

The excess hydride is decomposed at 0° C. with 25 ml of ethyl acetate and then with 100 ml of a 1° C. mixture of saturated NH4Cl and water. Filter the reaction mixture through a short pad of Celite and wash it thoroughly with ether. The combined organic layers are washed with saturated NaCl and dried (M g S 0
4). Concentration gives virtually pure 6 in quantitative yield: mp-67-68°C; IR (CC14): 364
0 (m), 3290 (s, b r), 2960
(s), 1425 (m)+1385 (m),
1245 (m), 1030 (m) cm"; IH
-NMR (CDCl2.TMS): 1.40 (s,
15H), 1.85 (br s.

Alcoholic OH, IH), 3.65 jbr, s.

2H), 6.6-7.3 (m, 3H), 9.05(
s+ Phenolic Odan, IH); 13C-NMR (C
DCl2. TMS) δ (off-resonance multiplicity): 25.45 (q).

29.99 (q), 34.97 (s).

39.75 (s), 74. 13 (t).

118.96 (d), 125.25 (d)
.

125.58 (d), 133. 33 (s
).

138.25 (s), 155.28 (s)
.

Preparation of 7 in 30 ml of dichloromethane 1. 78g (8,00I
Methanesulfonyl chloride (Ms Cl) 0.68 ml (8,8a+
mol) and triethylamine (E t 3 N )
Add 2.80 ml (20,0 asol) continuously. The reaction was stirred at 0° C. for 1 hour and poured into saturated NaCl.

The aqueous layer was extracted with ether and the combined organic phases were extracted with saturated NaCl.
1 and dry (MgSO4). Kugelrohr distillation (oven temperature -110°C, 0, 5
torr) to obtain 1.49 g (91%) of 7: to IR: 2960 (s), 2870 (
m), 1425 (m), 995 (m), 745-1
．． 1 (n) cm, H-NMR (CDCl2°TMS
) δ: 1.25 (s, 6H), 1.35 (s, 9H
), 4.15 (s, 2H), 6.7-7, 2 (m
, 3H); 13C-NMR (CD C13°TM
S) δ (off-resonance multiplicity): 27
．． 42 (q), 29. ．． 36 (q).

34.07 (s), 41.39 (s).

83.57 (t), 119.84 (d).

120.31(d), 124.58(d).

133.08 (s), 136.85 (s).

157.11 (s).

Preparation of 9 2.81 g in 40 ml of dichloromethane (12,710
1) 6, t-butyldimethylchlorosilane (t-Bu
Me2SiC1) 2.37sr (15,8m5ol) and 4-dimethylaminopyridine (DMAP) 0. 3
Triethylamine (E t 3N) 5.23 ml (38.0
add asol). The reaction mixture was stirred at 25° C. overnight and poured into the appropriate water. The aqueous layer is extracted with ether and the combined organic layers are washed with saturated NaCl and dried (Mg
SO4). The crude concentrated reaction solution was applied to a silica gel short column and 2% EtOAc/hexane (9 Rf-0,7
2) Elute directly into the round bottom flask. By concentration 4
．． Obtaining 06g (95%) of 9; IR (film): 3225 (s, br).

2950 (s), 2930 (s), 1385 (s)
, 1250 (s), 1050 (s).

-1,1 835 (s), 780 (s) am, H-NM
R(CDCl2.TMS) δ: 0.15 (s.

6H), 0.95 (s, 9H), 1.45
(s.

15H), 3. 70 (s, 2H),
6. 6-7, 3 (m, 3H), 9. 50
(s, IH).

Example 2 Production and 1.65g (8,10■-
A solution of 7.ol) was mixed with 4-pentinoyl chloride 8. 90 auaol and 1 stannic chloride,
05ml (8,90nmol) was continuously treated. The mixture is stirred at -78°C for 1 hour, then warmed to about -50°C and stirred there for 5 minutes. Then, the reaction solution was diluted with 0.1
Pour into N HCI and separate layers. The aqueous portion was extracted with ether and the combined organic phases were dissolved in saturated NaHCO3.
and saturated NaCl and then dried (MgS
O4). Flash chromatography (5% EtOA
c/hexane) to give 8A in 90% yield.

Example 3 Preparation of 11 9 (3n+mol) in dry CH2Cl2 (12ml)
) was cooled to -78°C, 4-pentenoyl chloride (3,3 mol) (n-butyllithium (1 eq., 0-25°C)) and then oxalyl chloride (1 eq., 2
5nC14 (prepared from the corresponding acid and used in situ) using a syringe, followed by 5nC14 (
0.375 ml) is added dropwise from a syringe while stirring under argon. After 30 minutes, the reaction solution was warmed to 0°C, stirred at that temperature for 5 minutes, and then the reaction was diluted with 3N MCI.
Let it stop for about 1 ml.

The reaction mixture was poured into 100 ml of water and extracted three times with 50 ml of ether each time. The combined ether layers are combined until the aqueous layer is neutral (pH
Rinse with 150 ml of water until test).

The ether layer is dried (Mg5O4), filtered, and concentrated in vacuo to yield crude silylated intermediate 10B.

10B is dissolved in THF (50 ml) and treated with 6.25 auaol of tetra-n-butylammonium fluoride trihydrate (TBAF) at 25°C.

After stirring for 1 hour, the mixture is poured into saturated NH4Cl and extracted with pentane. The combined organic portions are washed with saturated NaCl, dried over MgSO4, filtered, and concentrated in vacuo. The concentrate is purified by silica gel (sg) chromatography to obtain pure 11B.

11 B in 15 ml of acetone 4. 15 ml of Jones reagent (prepared from 6.65 g of sodium dichromate dihydrate and 45 ml of concentrated H2SO, diluted to 15 ml with water) are added to the 75 mmol solution at 0.degree.

The mixture is stirred at 0° C. for 15 minutes and then at room temperature overnight. The reaction solution is then poured into a mixture of water and ether and the layers are separated. The aqueous portion was extracted with ether and the combined organic phases were diluted with saturated NaHC03 and saturated NaCl.
Wash with water and then dry (MnSO4)
- Purify the crude product by flash chromatography using 10% EtOAc/hexanes, yielding 60%
Get 12B.

Example 4 Production of 13 11B in 50ml of dichloromethane 3. 30mra
Add pyridinium dichromate (PDC) to a solution of OI at 25°C.
) Add 1.36g (3,63na+ol).

The mixture is diluted with 100 ml of ether and stirred for 8 hours at room temperature before filtering the solid. Concentration followed by flash chromatography (15% EtOAc/hexanes) gives 13B in 30% yield and 12B in about 10% with IIB recovered at about 50%.

A skilled chemist would be able to prepare compounds of the present invention similar to compounds 8A, 12B and 13B by using appropriate raw materials CiY and making appropriate modifications to the preparation examples of Examples 3 and 4 above. is easily understood.

Example 14 Carrageenin Rat Paw Edema Test Male Sprague-Davl
ey) rat [Charles River Laboratory
es) ) were weighed and fasted overnight. The animals were then divided into 4 groups of 6 animals in each group according to body weight (with an average of about 145 g) so that each group had a similar average body weight (within 10 g).
- Divide into 6 groups.

The next morning, the animals are dosed with the test compound and then placed in side cages. For oral administration, the drug is suspended in 2% Tween 80 native 0.5% methylcellulose and released through a 5 ml gastric tube.

Pav volume ff1 (time 0) is measured in both hindpaws with a mercury displacement device equipped with a transducer and digital display. One hour after test compound administration, animals are placed in a plastic restrainer and 50 μl of a 1% (w/w) carrageenan solution in 0.9% saline is injected into the ventral surface of the left hind paw. Four hours after carrageenan injection, the constant volume is measured again.

Results are presented as mean percent foot volume inhibition for the test group compared to the control group. Statistical differences are one-dimensional (o
new way ) examined by analysis of variance.

Example 6 Pharmaceutical composition in tablet form Tablets are manufactured by conventional methods such as mixing and direct compression as follows: Ingredients mg/tablet Compound 8C200 Microcrystalline cellulose 100 Sodium starch glycolate 30 Stearic acid Magnesium When administered orally twice a day, the above composition significantly suppresses inflammation in patients with rheumatoid arthritis. Significant effects are also obtained by twice daily administration of this composition to osteoarthritis patients.

Similar results are obtained when compound 8 is formulated as above but
It can also be obtained in the case of tablets using 500 mg of Compound 13C or 100 mg of Compound 8D instead of 100 mg of C.

Example 7 Pharmaceutical composition in capsule form Capsules are manufactured by conventional methods and contain the following ingredients: Ingredient mg/capsule compound 8G
200 Lactose Fill Capsule Capsules substantially suppress symptoms in patients with rheumatoid arthritis or osteoarthritis when given once daily during the sun. Similar results were obtained when formulating as above but replacing compound 8C with compound 8A, 1
It is also obtained in the case of capsules with 2B, 13B, 12C, 13C or 8D.

Although specific embodiments of the invention have been described, those skilled in the art will appreciate that various changes and modifications to the compounds and compositions disclosed herein can be made without departing from the spirit and scope of the invention. It would be obvious if there was. The appended claims are intended to cover all such modifications that fall within the scope of the invention.

[Brief explanation of the drawing]

The figure is a route diagram for producing compounds of the invention. Applicant's representative: Mr. Sato

Claims (1)

[Claims] 1. A compound having the following structure: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula: (a) -A- is -CH_2-, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and ▲There are mathematical formulas, chemical formulas, tables, etc.▼; Preferably -A- is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and more preferably -CH_2
-; (b) -Y is selected from the group consisting of; 1) -(CR^1_2)_n-C≡C-H (n is an integer from 1 to about 6); 2)▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n is 0 to about 5
3) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (m is an integer from 1 to about 5
, and m+n is an integer from 1 to about 5); 4) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (n is 0 or 1
); 5)-(CR^1_2)_n-CR^3=CH_2(n
is an integer from about 2 to about 6); 6) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (n is from 0 to about 5
); 7) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (m is 1 to about 3
and m+n is an integer of 1 to about 3); 8) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (n is 0 to about 3
); 9)-(CR^1_2)_n-CR^3=C=CH_2
(n is an integer from 0 to about 6); 10) ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ (m + n is an integer from 0 to about 5)
; 11) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n is an integer from 0 to about 3); 12) - (CR^1_2)_n-CH(ZR^4)_2
(n is an integer from 1 to about 6); and 13) ▲Mathematical formulas, chemical formulas, tables, etc.▼ (n is an integer from 1 to about 5, m is an integer from 0 to about 4, and m+n is an integer of about 1 to about 5); and in the above formula, each -R^1 is independently -H, -
OR^3, -NR^3_2, -NR^3^+_3, -N
(R^3)C(O)R^3, -O_2CR^3, -CO
_2R^3, -C(O)NR^3_2, the group consisting of straight-chain or branched saturated alkyl groups having 1 to about 3 carbon atoms and straight-chain or branched unsaturated alkyl groups having 1 to about 3 carbon atoms or two -R^1s on the same carbon atom are =O or =CR^3_2; each -R^2 is independently -H, -OR^3, -NR
^3_2, -NR^3^+_3, -N(R^3)C(O
)R^3, -O_2CR^3, -CO_2R^3, -C
(O)NR^3_2, selected from the group consisting of straight chain or branched saturated alkyl groups having 1 to about 3 carbon atoms and straight chain or branched unsaturated alkyl groups having 1 to about 2 carbon atoms; Or two -R on the same carbon atom
^2 is =O or =CR^3_2; each -R^3 is independently selected from the group consisting of -H, methyl and ethyl; each -R^4 is each independently -CH_3 and -C
H_2CH_3, or -R^4 is selected from the group consisting of H_2CH_3, or -R^4 is selected from the group consisting of -(CH_2
)_2- and -(CH_2)_3-; each -Z- is independently -O-, -
S-, -NH- and -NR^4-] or a pharmaceutically acceptable salt thereof. 2, (a) Each -R^1 and -R^2 are each independently -H
, -OH, methyl, ethyl, or two -R^1 or -R^ on the same carbon atom
2 is =O or =CH_2; further up to about 2 -R^1 or -R^2 groups are groups other than -H; preferably each -R^1 and -R^2 is - (b) each -R^3 is -H; (c) each -R^4 is methyl or both -
The R^4 groups are groups that together form a cyclic acetal.
(CH_2)_2-; and (d) each -Z- is each independently selected from the group consisting of -O- or -S-; preferably each -Z- is -O-
The compound according to claim 1. 3, -Y group is: 1)-(CR^1_2)_n-C≡CH (n is 1 to about 6
2) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n is 0 to about 5
3) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (n is 0 to about 3
); 4) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n is 0 or 1
); 5)-(CR^1_2)_n-CH(ZR^4)_2(
n is an integer from 1 to about 6); 6) ▲Mathematical formulas, chemical formulas, tables, etc.▼(n is 1 to about 5
); and 7) ▲Mathematical formulas, chemical formulas, tables, etc.▼(n is 1 to about 3
3. The compound according to claim 1 or 2, wherein the compound is selected from the group consisting of: 4. -Y group is: 1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n is 0 to about 3
2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (n is 1 to about 5
); and 3) ▲Mathematical formulas, chemical formulas, tables, etc.▼(n is 0 to about 5
preferably n is an integer of 3; preferably n is 3;
A compound according to claim 1 or 2. 5. -Y is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (n is an integer from 0 to 5, preferably n is 3)
The compound according to claim 1 or 2, which is 6. The compound according to claim 1 or 2, wherein -Y is ▲a mathematical formula, a chemical formula, a table, etc.▼. 7. A pharmaceutical composition comprising: (a) a safe and effective amount of the anti-inflammatory compound according to any one of claims 1 to 6; and (b) a pharmaceutically acceptable carrier. 8.Claim 1 in the manufacture of a drug for treating inflammation
Use of a compound according to any one of -6.